Our laboratory is focused on using a genetic approach to isolate and understand genes contributing to the pathogenesis of the inherited forms of breast cancer, Long QT Syndrome and neural tube defects.We were previously engaged in the positional cloning of the BRCA1 gene. Through the use of multiple transcript isolation methods we have cloned and mapped the precise location of over 25 genes to this region of chromosome 17. The resulting transcript map provides a detailed description of the functional anatomy of this region of the genome. With the recent identification of the BRCA1 gene, our laboratory is now focused on addressing questions of its function. We recently completed a study of 70 affected women from high risk families. Over 20 pathologic BRCA1 mutations have been defined at the molecular level in this study population. The majority of these resulted in the disruption of the BRCA1 coding sequence (frame shifts or terminations). These results are consistent with the prediction that BRCA1 is a tumor suppressor gene. Direct studies of the BRCA1 protein with antibody reagents and expression are currenty underway. The second area of investigation involves study of the gene itself. It is estimated that as many as one in three hundred individuals carries a BRCA1 mutation. Much could be learned about the BRCA1 gene by surveying for naturally existing population variants and pathological mutations. BRCA1 is a relatively large gene and the number of different mutations present in the population is likely to be great. Along these lines, we are currently investigating new high efficiency methods of mutation detection. Similar lines of investigation are now underway for two other genes. In collaboration with Mark Russell at the University of Michigan, we have been able to narrow the candidate interval for the chromosome 11 form of Long QT syndrome. New genetic markers are now being isolated to help refine this interval. We are also in the process of cloning the human gene for methionine synthase (with James Mills, NICHD and Ruma Banerjee, U.NB, Lincoln). It is likely that this gene plays a role in the pathogenesis of neural tube defects and vascular disease.